Arylation process for preparation of chiral catalysts for ketone reduction

ABSTRACT

The chiral catalyst of general structure 1, or its enantiomer ##STR1## is prepared by treating the corresponding N-carboxy anhydride of structure 2 ##STR2## with an aryl metal, especially a phenyl metal such as an aryl magnesium halide, aryl lithium, aryl zinc or aryl cesium, to form a 1,1-diaryl-methanol of structure 3 ##STR3## followed by treatment with a compound of structure, 4 ##STR4## The catalyst, wherein R is aromatic, is novel and in some cases superior to the catalyst wherein R is alkyl or aralkyl in directing the chirality of borane-dimethyl sulfide reductions of ketones to secondary alcohols.

SUMMARY OF THE INVENTION

This invention is concerned with a novel process for preparing adiarylmethanol 3 especially a 1,1-diarylprolinol, which comprisestreating the corresponding N-carboxy anhydride 2 with an aryl metal,especially a phenyl metal, such as an aryl lithium, aryl zinc, arylcesium or aryl magnesium halide, especially the chloride: ##STR5##

The invention is also concerned with a process for preparing a chiralcatalyst 1 by treating the 1,1-diarylmethanol with a trisubstitutedboroxin 4; ##STR6##

The invention is also concerned with the novel catalyst 1, wherein R isan aromatic group, either unsubstituted or substituted.

The catalyst produced by the novel process of this invention is usefulfor directing the chirality of reductions of ketones with boranes suchas diborane, borane-dimethyl sulfide, or borane-THF to chiral secondaryalcohols such as in the synthesis of a chiral intermediate 5 in thesynthesis of the known carbonic anhydrase inhibitor 6 useful in thetreatment of ocular hypertension and glaucoma. ##STR7##

BACKGROUND OF THE INVENTION

(S)-1,1-Diphenylprolinol the principal compound of structure 3 is aknown compound and has been prepared by a variety of processes, allinvolving a fully protected pyrrolidine. See for example Enders et al.,Org. Synth., Col. Vol. 5, 542-549; Corey et al., J. Amer. Chem. Soc.,1987, 109, 7926-7927; French Patent FR 3638M, 1965; Kapfhammer, et al.Hoppe-Seylers Zeit. Physiol. Chem. 1933, 223, 43-52; German Patent DE3609152A1, 1987; Corey et al., J. Amer. Chem. Soc., 1987, 109 5551-5553;J. Org. Chem. 1988, 53, 2861-2863; Enders et al., Bull Soc. Chem. Belg.,1988, 97, 691-704. These prior art processes involve multiple steps andrather low overall yields.

For example preparation of (S)-1,1-diphenylprolinol via the proceduredescribed in the literature [Corey et. al., J. Am. Chem. Soc. 1987, 109,5551-5553] afforded a 30-40% overall yield of the amino-alcohol from(S)-proline. The process required multiple isolations[N-(benzyloxycarbonyl)-(S)-proline (solid, commerically available),N-(benzyloxycarbonyl)-(S)-proline methyl ester (viscous oil), and(S)-1,1-diphenylprolinol hydrochloride (solid, precipitated from diethylether), and (S)-1,1-diphenylprolinol (solid recrystallized fromwater/methanol)]. The Grignard addition toN-benzyloxycarbonyl)-(S)-proline methyl ester required a large excess (8equiv) of phenylmagnesium chloride. The inital addition to form theintermediate 1,1-diphenylprolinol oxazolidinone occurs quickly at 0° C.The addition of phenylmagnesium chloride to the oxazolidinone affordingthe desired product, however, is much slower--requiring 12-18 hours atroom temperature. Isolation of the amino-alcohol from the large excessof magnesium salts also was a problem--requiring multiple extractionsfrom a magnesium hydroxide gel. The resultant product had anenantiomeric purity of 99:1 (S:R) by capillary GC (DB-23) of the Mosheramide derivative. ##STR8##

The methods reported for preparation of structure 1 (n═1, Ar═Ph, R═Me,R¹, R² ═H), include reaction of the corresponding prolinol withmethylboronic acid (1.1 equiv:1) in toluene at 23° C. in the presence of4 Å molecular sieves for 1.5 hours; or 2) in toluene at reflux for 3hours using a Dean-Stark trap for water removal; both followed byevaporation of solvent, and molecular distillation (0.1 mm, 170° C.)(Corey et al., J. Amer. Chem Soc., 1987 109, 7925-7926). An Alternatemethod reported for preparation of structure 1 (n═1, Ar═2-naphthyl,R═Me, R¹ R² ═H) involved heating a toluene solution of the correspondingprolinol and methylboronic acid (1.2 equiv) at reflux for 10 hours usinga Soxhlet extractor containing 4 Å molecular sieves (Corey et al.,Tetrahedron Lett., 1989, 30, 6275-6278). The key to these procedures isirreversible removal of two molecules of water, thus driving thereaction to completion. Chiral reductions using oxazaborolidine preparedvia these methods provided erratic results with respect to yields andenantiomeric purity of the reduction products.

Now, with the present invention there is provided a novel improvedprocedure for preparation of the diarylmethanol 3; a novel improvedmethod for the preparation of the oxazaborolidine catalyst, 1; and novelimproved catalysts.

DETAILED DESCRIPTION OF THE INVENTION

The novel process for preparation of the diarylmethanol 3 comprisesreacting an N-carboxyanhydride 2 with an aryl Grignard reagent: ##STR9##wherein n is 1 or 2; R¹ and R² independently represent hydrogen, C₁₋₃alkyl or joined together represent with the carbons to which they areattached a benzo group or a double bond; Ar is (1) 2-naphthyl, (2)phenyl, or (3) phenyl substituted in the meta- and or para- positionswith one or more of (i) halo, such as fluoro or chloro, (ii) C₁₋₄ alkyl,(iii) CF₃ or (iv) C₁₋₄ alkoxy.

The N-carboxyanhydride, 2, is synthesized from the corresponding aminoacid such as (S)-proline in >95% yield by reaction with phosgene,diphosgene or triphosgene in THF followed by addition of triethylamineand filtration to remove the resultant triethylamine hydrochloride asdescribed by Fuller et al., Biopolymers, 1976, 15, 1869-1871.

The novel process for converting the N-carboxyanhydride, 2, to thediarylmethanol, 3, comprises reacting an ArMgHal preferably ArMgCl,Grignard reagent with the N-carboxyanhydride in an ethereal solvent suchas THF, diethyl ether or 1,2-dimethoxyethane, preferably THF at about-26° to 10° C. over a period of about 2 to 5 hours. It is preferred toadd the N-carboxyanhydride to the Grignard reagent slowly (about 1L/hour) to provide maximum yield and minimum racemization.

The diarylmethanol is isolated by slowly quenching the reaction withaqueous acid, preferably dilute sulfuric acid at about 0°-20° C.,filtration to remove sulfate salts, concentration to a small volume andfiltration to collect the sulfate salt of the diaryl methanol product 3which can be further purified by washing with water and ethyl acetateand dried.

The novel process of this invention for preparation of the B-methyloxazaborolidine catalyst (precursor) comprises reacting thediarylmethanol with a trimethylboroxine; ##STR10##

The process for the preparation of B-methyloxazaborolidines comprisesthe reaction of trimethylboroxine (0.67 to 1.0 equiv) with thediarylmethanol in an organic solvent such as toluene, benzene, xylene,chlorobenzene or the like at about 0° C. to 30° C. for about 0.5 to 4hours until formation of the intermediate 5 is complete. The solution isthen heated at about 80° C. to 150° C. for about 1 to 4 hours. Thesolvent is partially evaporated followed by multipleadditions/concentrations of toluene or benzene to ensure completeremoval of water and the methylboronic acid byproduct.

The novel intermediate of this invention has the structural formula 5;wherein n, Ar, R¹ and R² are as previously defined. It is preferred thatn be 1, R¹ and R² be hydrogen, and that Ar be phenyl. ##STR11##

The novel process of this invention for preparation of the B-C₂₋₄ alkyloxazaborolidine or B-aryl oxazaboro lidine catalyst (precursor)comprises reacting the diaryl methanol with a boroxine; ##STR12##wherein R is (1) C₂₋₄ alkyl, preferably butyl, (2) phenyl, (3) phenylsubstituted with one or more of (i) halo, such as fluoro or chloro, (ii)C₁₋₄ alkyl, (iii) CF₃, or (iv) C₁₋₄ alkoxy.

The process comprises the reaction of a boroxine (0.33 equiv) with thediarylmethanol in an organic solvent such as toluene, benzene, xylene,chlorobenzene or the like at about 0° C. to 30° C. for about 0.5 to 4hours, then at 80° C. to 150° C. for about 12 to 24 hours withconcurrent removal of water, using a Dean-Stark trap, molecular sieves,or azeo tropic distillation.

The novel catalyst of this invention has structural formula 1; ##STR13##wherein n, Ar, R¹ and R² are as previously defined and R is (1) phenyl,(2) phenyl substituted with one or more of (i) halo, such as fluoro orchloro, (ii) C₁₋₄ alkyl, (iii) CF₃, or (iv) C₁₋₄ alkoxy.

It is prefered that n be 1, R¹ and R² be hydrogen, and that Ar bephenyl. It is also prefered that R be phenyl substituted with 4-fluoroor 4-C₁₋₄ alkyl group, especially methyl.

EXAMPLES General

Melting points were determined on a Haake-Buchler melting pointapparatus and are uncorrected. IR spectra were recorded on aPerkin-Elmer 1420 (as solutions in CCl₄) or a Nicolet 60SX FTIRspectrometer on microcrystalline solids using a Spectrascope accessoryrun at 4 cm⁻¹ resolution. NMR spectra were recorded in deuterochloroformor deuteroacetonitrile on a Bruker AM-250 (¹ H, ¹³ C), WM-250 (¹ H, ¹¹B, ¹³ C), or AM-400 (¹ H, ¹¹ B, ¹³ C) spectrometer. ¹ H chemical shiftsare reported in ppm from an internal stand ard of residual chloroform(7.27 ppm) or acetonitrile (1.93 ppm). ¹¹ B chemical shifts are reportedin ppm from an external reference of boron trifluoride etherate (0.0ppm). ¹³ C chemical shifts are reported in ppm from the central peak ofdeuterochloroform (77.0 ppm) or deuteroacetonitrile (1.3 ppm). Specificrotations were determined on a Perkin-Elmer 241 polarimeter.Concentrations (c) for specific rotations are reported in units of g/100mL. Analytical gas chromatography (GC) was carried out on aHewlett-Packard 5890A gas chromatograph equipped with a 7673Aauto-sampler, split-mode injector, and flame-ionization detector, withhelium as the carrier gas. The following capillary columns wereemployed: 30 m×0.32 mm DB-1 (J&W Associates) and 30 m×0.32 mm DB-23 (J&WAssociates). Analytical high-performance liquid chromatography (HPLC)was carried out on a Hewlett-Packard Modular 1050 HPLC (quaternary pumpand programmable variable-wavelength detector) using Column A: 250×0.46mm DuPont Zorbax RX or Column B: 250×0.46 mm E. Merck Chirasphere.Analytical thin layer chromatography (TLC) was carried out on EM 0.25 mmsilica gel 60F HPTLC plates using the following solvent systems: solventA (45:45:9:1 hexane/dichloromethane/isopropanol/28% aq NH₄ OH: solvent B(7:3 hexane/EtOAc). Visualization was accomplished with UV light and/orby spraying with aqueous cerric ammonium molybdate followed by heating.Mass spectra were obtained on a Finnigan-MAT TSQ 70B Mass Spectrometerusing either GC/MS with chemical ionization (NH₃) or FAB/MS using aDTT/DTE matrix. Combustion analyses were obtained in-house from ourAnalytical Research Department.

Reactions were carried out under an atmosphere of dry N₂. As necessaryEt₃ N, THF and toluene were dried over 3 Å or 4 Å molecular sieves.Residual water content was determined by Karl Fisher (KF) titration.(S)-Proline was obtained from Ajinomoto, (R)-proline from Tanabe U.S.A.,Inc. Phosgene (1.93M in toluene) was obtained from Fluka.Phenylmagnesium chloride (2M in THF) was obtained from BoulderScientific. Other Grignard reagents were either obtained from Aldrich,or prepared from the corresponding aryl bromide. Trimethylboroxine andn-butylboronic acid were obtained from Aldrich. Triarylboroxines wereprepared from the corresponding arylboronic acids by heating a tol uenesolution at reflux for 3-4 hours using a Dean-Stark trap for waterremoval, followed by evaporation of the solvent. (R)-MTPA (Aldrich) wasconverted to the acid chloride using oxalyl chloride (1.2 equiv) andcatalytic DMF (0.05 equiv) in dichloromethane at 20°-25° C. for 4 hoursfollowed by Kugelrohr distillation (45° C., 0.1 mBar).

EXAMPLE 1 Step A: Preparation of (S)-Tetrahydro[1H,3H]pyrrolo-[1,2-c]oxazole-1,3-dione

A 5-L, three necked flask fitted, with a mechanical stirrer, nitrogeninlet tube, 1-L addition funnel, and teflon coated thermocouple probe,containing dry THF (1.15 L), was charged with (S)-proline (115 g, 1.00mol). To the well stirred, cooled (15°-20° C.) suspension was added asolution of phosgene in toluene (1.93M, 622 mL, 1.20 mol) over a 0.5-1.0hour period, maintaining the internal temperature at 15°-20° C. Caution:phosgene is an insidious poison. All manipulations with phosgene shouldbe performed in a hood with good ventilation. Any excess phosgene shouldbe decomposed in cold aqueous base. After the phosgene addition wascomplete, the mixture was warmed to 30°-40° C. and aged for 0.5 hour.During this time the mixture became homogeneous as proline reacted withphosgene to afford the intermediate N-carbamoyl chloride. Oncehomogeneous, the reaction mixture was aged an additional 0.5 hour at30°-35° C., then cooled to 15°-20° C. While maintaining the internaltemperature at 15°-20° C., the reaction mixture was concentrated invacuo (1000 down to 50 mBar) to a volume of about 150 mL. Caution:hydrogen chloride (1 mol) and excess phosgene (200 mmol) are removedduring the distillation. The use of appropriate traps, and venting ofthe vacuum pump to the hood is required. The reaction can be assayed atthis point by ¹ H NMR: (about 30 μL dissolved in 0.6 mL CDCl₃)δ11.5-10.0 (br s, 1H, CO₂ H), 7.3-7.1 (m, toluene), 4.62 (dd, 0.4H,C2--H rotamer), 4.50 (dd, 0.6H, C2--H rotamer), 3.9-3.5 (m, 2H, C5--H₂),2.5-1.8 (m, 4H, C3--H₂, C4--H₂). [The spectrum should not containresonances at δ4.9 (dd, 0.4H, C2--H rotamer) and 4.7 (dd, 0.6H, C2--Hrotamer) corresponding to proline N-carbamoyl chloride, acid chloride.]The residue was dissolved in dry THF (1.15 L), and the solution cooledto 0°-5° C. With good agitation, dry Et₃ N (106 g, 1.05 mol) was addedover 15 minute while maintaining the internal temperature at 0°-5° C.After the addition was complete, the mixture was aged for 0.5 hour at0°-5° C., then filtered through an enclosed, medium frit, sintered glassfunnel. The resultant cake of Et₃ N HCl was washed with THF (3×200 mL).The filtrate and THF washes were combined to afford a solutioncontaining product (about 0.95-1.0 mol) in THF (about 1.75 L) that wasused immediately "as is" without further purification.

For analysis, a portion of the THF solution was concentrated in vacuo(20° C., 50 mBar) and the resultant white solid dried in vacuo (20° C.,0.01 mBar) overnight: mp 51°-52° C.; IR (CCl₄): 2980, 1845, 1780, 1350,950, 920 cm⁻¹ ; ¹ H NMR (CDCl₃) δ4.34 (dd, J=7.4, 8.7 Hz, 1H, C2--H),3.72-3.68 (m, 1H, C5--H₂), 3.32-3.18 (m, 1H, C5--H₂), 2.4-1.8 (m, 4H,C3--H₂, C4--H₂); ¹³ C NMR (CDCl₃) δ168.9 (C3), 154.9 (C1), 63.1 (C3a),46.5 (C6), 27.6 (C4), 26.9 (C5).

Anal. Calcd for C₆ H₇ NO₃ : C, 51.06; H, 4.96; N, 9.93. Found: C, 51.23;H, 4.84; N, 9.65.

Step B: Preparation of (S)-α,α-Diphenyl-2-pyrrolidinemethanol

A 5-L three necked flask fitted with a mechanical stirrer, nitrogeninlet tube, 2-L addition funnel containing the THF solution of productfrom Step A, and teflon coated thermocouple probe, was charged with asolution of phenyl magnesium chloride in THF (2.0M, 1.5 L, 3.0 mol). TheGrignard reagent was cooled to -15° C. The THF solution of product fromStep A (about 0.95-1.0 mol) was added over a 1 hour period whilemaintaining the internal temperature at -10° to -15° C. After theaddition was complete, the mixture was aged for 3 hours at -15° C. and 1hour at 0° C. The reaction was quenched into a 12-L mechanically stirredflask, containing a pre-cooled (0° C.) solution of 2M aqueous H₂ SO₄(2.0 L, 4.0 mol), over a 0.5-1.0 hour period while maintaining theinternal temperature below 20° C. During the quench, a thick whiteprecipitate of MgSO₄ formed. The mixture was agitated for 1 hour at 0°C., and filtered through a 3-L, medium frit, sintered glass funnel. TheMgSO₄ cake was washed free of residual product with THF (3×1.0 L). Thefiltrate and THF washes were combined and concentrated at atmosphericpressure to a volume of 2.0 L. Caution: benzene (about 82 g), formedduring the quench of excess PhMgCl, is removed during the concentration.The product as its sulfate salt, Ph₂ CO, and Ph₃ COH precipitate duringthe concentration. The mixture was cooled to 0°-5° C., aged 1 hour, andfiltered. The cake was washed with H₂ O (2×200 mL) to remove excess H₂SO₄, and EtOAc (3×350 mL) to remove the Ph₂ CO and Ph₃ COH. The cake wasdried in vacuo (40° C., 50 mBar) affording 221 g (73% from proline) ofthe sulfate salt of the product as a white solid: mp 275°-290° C. (dec).

Anal. Calcd for C₃₄ H₄₀ N₂ O₆ S: C, 67.52; H, 6.67; N, 4.63. Found: C,67.75; H, 6.67; N, 4.51.

A portion of the sulfate salt was converted to the free base as follows:to a mechanically stirred solution of THF (50 mL) and 2M aqueous NaOH(50 mL, 100 mmol) at 20° C. was added the sulfate salt (15.1 g, 50.0mmol). The mixture was stirred at 20° C. until all solids dissolved, andwas then diluted with toluene (200 mL). The two-phase mixture wasfiltered through a medium frit sintered-glass funnel, partitioned, andthe organic layer washed with H₂ O (25 mL). The organic layer wasconcentrated in vacuo (50° C., 1 mBar) affording 12.5 g (99% yield) ofproduct as a colorless oil that crystallized on standing. An analyticalsample was prepared by recrystallization from hexane: mp 79°-79.5° C.[Lit. mp 76.5°-77.5° C. (H₂ O/MeOH); mp 80°-82° C. (EtOH)]; IR (CCl₄)3600-3300 (br), 3170, 3140, 2980, 2790, 1490, 1450, 1400, 1170 cm⁻¹ ; ¹H NMR (CDCl₃) δ7.7-7.5 (m, 4H, Ar--H), 7.4-7.1 (m, 6H, Ar--H), 4.65 (s,1H, O--H), 4.3 (t, J=7.4 Hz, 1H, C2--H), 3.1-2.9 (m, 2H, C5--H₂),1.9-1.5 (m, 5H, C3--H₂, C4--H₂, N--H); ¹³ C NMR (CDCl₃) δ148.21, 145.41(C1', C1"), 128.24, 127.98 (C3', C3", C5', C5"), 126.46, 126.36 (C4',C4"), 125.88, 125.55 (C2', C2", C6', C6"), 77.1 (Cα), 64.41 (C2), 46.68(C5), 26.30 (C3), 25.51 (C4); GC/MS: [ M+H]⁺ at m/z 254.1; TLC (solventA) R_(f) =0.32; [α]₅₈₉ ²¹ -54.3° (c=0.261, MeOH) [Lit. [α]₅₈₉ ²⁴ -58.8°(c=3.0, MeOH)].

Anal. Calcd for C₁₇ H₁₉ NO: C, 80.60; H, 7.50; N, 5.53. Found: C, 80.80;H, 7.64; N, 5.49.

Chiral Assay: To a magnetically stirred suspension of Step B product(sulfate salt) (30 mg, 100 μmol) in THF (1 mL) was added 1.0M aq NaOH(210 μL, 210 μmol). The mixture was stirred until all of the soliddissolved (about 15 minute), then (R)-MTPA acid chloride (27 mg, 107μmol) was added, and the mixture stirred for 1 hour at 20° C. Thereaction can be monitored by TLC (solvent B) Step B product (R_(f)=0.05), (R,R)-derivative (R_(f) =0.78), (R,S)-derivative (R_(f) =0.71).After completion, the mixture was diluted into hexane (9 mL),centrifuged, and the upper, organic layer eluted through a Baker silicaSPE (1 g) column (previously washed with hexane). The column was elutedwith additional 8:2 (v/v) hexane/THF (5 mL). The combined eluate wasanalyzed by either GC (DB-23, 250° C.) to detect 0.3% of the(R,R)-derivative (19.1 minute) and 99.7% of the (R,S)-derivative (20.7minute); or HPLC (Zorbax Si, 9:1 hexane/THF, 210 nm) to detect 0.3% ofthe (R,R)-derivative (k'=1.21) and 99.7% of the (R,S)-derivative(k'=1.66).

Employing the procedure substantially as described in Example 1, Step B,but substituting for the phenylmagnesium chloride used therein anequimolecular amount of the Grignard reagents depicted in Table I, thereare produced the diarylmethanols also described in Table I. ##STR14##

                                      TABLE I                                     __________________________________________________________________________    Example                                                                            Ar        Yield                                                                             m. p. (°C.)                                                                  [α].sub.589.sup.22                             __________________________________________________________________________    2    4-F--C.sub.6 H.sub.4 --                                                                 90  89.5-90                                                                             -48.5° (c = 0.323, MeOH)                      3    4-Cl--C.sub.6 H.sub.4 --                                                                59  114.5-115                                                                           -37.7° (c = 0.339, MeOH)                      4    4-CH.sub.3 --C.sub.6 H.sub.4 --                                                         57    94-94.5                                                                           -43.4° (c = 0.305, MeOH)                      5    4-CF.sub.3 --C.sub.6 H.sub.4 --.sup.(1)                                                 46   .sup. 280-300.sup.(2)                                                              -34.2° (c = 0.789, MeOH)                      6    4-t--Bu--C.sub.6 H.sub.4 --                                                             50  165.7-166.1                                                                         -25.1° (c = 0.389, MeOH)                      7    4-CH.sub.3 O--C.sub.6 H.sub.4 --.sup.(3)                                                53  --    -44.1° (c = 0.607, MeOH)                      8    3-Cl--C.sub.6 H.sub.4 --.sup.(3)                                                        62  --    -49.1° (c = 0.804, MeOH)                      9    3,5-Cl.sub.2 --C.sub.6 H.sub.3 --                                                       68  118-119                                                                             -36.6° (c =  1.409, MeOH)                     10   3,5-(CH.sub.3).sub.2 --C.sub.6 H.sub.3 --                                               60  97.5-98.0                                                                           -63.0° (c = 0.318, MeOH)                      11   2-naphthyl                                                                              64  142.5-143.5                                                                         -99.1° (c = 0.702, MeOH)                      __________________________________________________________________________     .sup.(1) Product is an oil. It was purified by conversion to its HCl salt     recrystallization, and conversion to free base. Yield and rotation are of     the purified oily product.                                                    .sup.(2) Melting point of the HCl salt.                                       .sup.(3) Product is an oil. It was purified by liquid chromatography on       silica gel. Yield and rotation are of the purified oily product.         

EXAMPLE 12 Preparation of (S)-α,α-Diphenyl-2-pyrrolidinemethanol-boranecomplex

A 250 mL three necked flask fitted with a mechanical stirrer, nitrogeninlet tube, and teflon coated thermocouple probe, was charged with asolution of the free base product of Example 1 Step B (20.7 g, 81.7mmol) in dry toluene (100 mL). To the stirred solution at 20° C. wasadded borane-methyl sulfide (10M, 10.0 mL, 100 mmol) over 5 minutes viasyringe. The borane reacted immediately in an exothermic reaction(raising the internal temperature from 20° C. to 32° C.) forming a thickwhite precipitate. With continued stirring, the mixture was allowed tocool to room temperature (20° C.) over a 1 hour period. The mixture wasfiltered, and the product cake washed with dry toluene (25 mL). Theproduct was dried in vacuo (20° C., 0.01 mBar) to constant weight. Yield15.7 g (72%) of a white crystal line solid. m.p. 130°-132° C. (dec). ¹ HNMR (CDCl₃) δ7.7-7.1 (m, 10H, Ar--H), 5.15 (s, 1H, --OH), 4.5 (br, 1H,--NH), 4.2 (m, 1H, C2--H), 3.25 (m, 2H, C5--H₂), 2.6 (m, 1H, C4--H), 2.3(m, 1H, C4--H), 1.85 (m, 1 H, C3--H), 1.6 (m, 1H, C3--H), 2.1-0.7 (br,3H, BH₃). ¹³ C NMR (CDCl₃) δ145.8, 144.5 (C1', C1"), 129.1, 128.2 (C3',C5', C3", C5"), 127.4, 127.0 (C4', C4"), 125.2, 125.1 (C2', C6', C2",C6"), 76.5 (Cα), 69.6 (C2), 55.6 (C5), 20.6 (C4), 19.9 (C3).

Anal. Calcd for C₁₇ H₂₃ BNO: C, 76.14; H, 8.64; N, 5.22. Found: C,xx.xx; H, x,xx; N, x.xx.

EXAMPLE 13 Preparation of(S)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol

A 3-L, three necked flask fitted with a mechanical stirrer, nitrogeninlet tube, and teflon coated thermocouple, was charged with the sulfatesalt of the product of Example 1, Step B (89.1 g, 295 mmol), THF (300mL), and 2M aqueous NaOH (300 mL). The mixture was stirred at 20°-25° C.until all of the solid dissolved (about 0.5 hour). Toluene (1.2 L) wasadded, the mixture stirred an additional 0.5 hour, filtered through amedium frit sintered glass funnel, and partitioned. The upper (product)layer was washed with water (150 mL), and concentrated (1 atm) to avolume of about 500 mL. The toluene solution was cooled to 20°-25° C.and charged with trimethylboroxine (24.7 g, 197 mmol). The temperatureof the mixture rose about 5° C., and a white precipitate of intermediate5 formed. The mixture was aged 0.5 hour at 20°-25° C., then heated atreflux for 1-2 hours. Toluene (500 mL) was added, and the mixtureconcentrated (1 atm) to a volume of about 300 mL. The toluene addition,followed by concentration was repeated two times to insure completeremoval of water and excess methylboronic acid (as trimethylboroxine).The suitability of the catalyst was determined by both capillary GC:(DB-1, 200° C.) <1% starting material (5.5 minute), >99% product (4.9minute), and ¹ H NMR: (CDCl₃) no starting material δ4.3 (t),trimethylboroxine δ0.45 (s), intermediate 5 δ0.35 to -0.50 (multipleB--CH₃ singlets), and/or water addition product δ-0.25 (br, B--CH₃). Thetoluene solution of oxazaborolidine (about 1.0M), stored under anatmosphere of N₂ protected from moisture, was used "as is" as a catalystfor the enantioselective reduction of ketones with borane.

For analysis, a portion of the toluene solution (10.0 mL) wasconcentrated in vacuo (50° C., 0.001 mBar) to afford 2.77 g of productas a white solid: mp 79°-81° C. [Lit. mp 74°-87° C.]; IR (CCl₄) 2960,2880, 1440, 1330, 1310, 1235, 1000 cm⁻¹ ; ¹ H NMR (0.2M in CDCl₃)δ7.65-7.15 (m, 10H, Ar--H), 4.4 (dd, J=5.8, 10.0 Hz, 1H, C3a--H),3.45-3.30 (m, 1H, C6--H), 3.15-3.00 (m, 1H, C6--H), 1.90-1.55 (m, 3H,C4--H, C5--H₂), 0.95-0.75 (m, 1H, C4--H), 0.40 (s, 3H, BCH₃); ¹¹ B NMR(0.2M in CDCl₃) δ34.3; ¹³ C NMR (0.2M in CDCl₃) δ147.6, 144.0 (C1',C1"), 128.2, 127.7 (C3', C3", C5', C5"), 127.1, 126.6 (C4', C4"), 126.3,126.2 (C2', C2", C6', C6"), 87.8 (C3), 72.7 (C3a), 42.9 (C6), 30.2 (C4),26.4 (C5), -5.6 (br, B--CH₃). FAB/MS (DTT/DTE matrix): [M+H]⁺ at m/z278.1. Isotopic cluster consistent with the presence of one boron.

Anal. Calcd for C₁₈ H₂₀ BNO: C, 78.00; H, 7.27; N, 5.05. Found: C,77.81; H, 7.37; N, 4.91.

EXAMPLE 14 Preparation of Intermediate 5

To a magnetically stirred solution of the free base product of Example1, Step B (5.06 g, 20.0 mmol) in dry toluene (20 mL) at 20° C. was addedtrimethylboroxine (1.67 g, 13.3 mmol). The reaction was exothermic,raising the temperature to 33° C. The solution was allowed to cool to20° C., then aged at that temperature for 1 hour. The resultant solidwas isolated by filtration. The solid was dried in vacuo (45° C., 0.1mBar) to afford 6.07 g (90%) of intermediate 5. An analytical sample wasprepared by recrystallization from EtOAc: mp 147°-148° C.; IR (solid)3435, 3270, 3066-2885, 1596, 1492, 1447, 1384, 1302, 1247, 1141, 1046,1030, 1015, 1006, 762, 752, 717, 701; ¹ H NMR (CD₃ CN, majordiasteromer) δ7.66 (m, 2H, o--Ar--H), 7.47 (m, 2H, o--Ar--H), 7.3-7.1(overlapping m, 6H, Ar--H), 6.37 (s, 1H, B--OH), 5.13 (br, 1H, NH), 4.68(dt, J=11.1, 6.5, 1H, C3a--H), 3.39 (m, 1H, C6--H), 2.99 (m, 1H, C6--H),1.9-1.7 (overlapping m, 3H, C5--H₂, C4--H), 1.44 (m, 1H, C4--H), 0.09(s, 3H, --OB(OH)CH₃), -0.49 (s, 3H, B1--CH₃); ¹¹ B NMR (CDCl₃, majordiasteromer) δ30.4 (--OB(OH)CH₃), 7.8 (B1); ¹³ C NMR (CD₃ CN, majordiasteromer) δ148.4, 147.9 (C1', C1"), 129.0, 128.8 (C3', C5', C3",C5"), 127.7, 127.2 (C4', C4"), 126.8, 126.1 (C2', C6', C2", C6"), 83.6(C3), 68.6 (C3a), 45.6 (C6), 28.7 (C4), 24.6 (C5), 7.0 (v br, B1--CH₃),-0.2 (v br, --OB(OH)C₃). FAB/MS (DTT/DTE matrix): [M+H]⁺ at m/z 338.2.Isotopic cluster consistent with the presence of two borons.

Anal. Calcd for C₁₉ H₂₅ B₂ NO₃ : C, 67.71; H, 7.48; N, 4.16. Found: C,67.59; H, 7.47; N, 4.15.

Employing the procedure substantially as described in Example 13, butsubstituting for the diphenylmethanol used therein, comparable amountsof the diarylmethanols described in Table II, there were produced theB-methyl oxazaborolidines also described in Table II: ##STR15##

                  TABLE II                                                        ______________________________________                                        Example      Ar           Purity (%)                                          ______________________________________                                        15           4-F--C.sub.6 H.sub.4 --.sup.(1)                                                            98                                                  16           4-Cl--C.sub.6 H.sub.4 --.sup.(1)                                                           99                                                  17           4-CH.sub.3 --C.sub.6 H.sub.4 --                                                            99                                                  18           4-CF.sub.3 --C.sub.6 H.sub.4 --.sup.(1)                                                    99                                                  19           4-t-Bu-C.sub.6 H.sub.4 --                                                                  99                                                  20           4-CH.sub.3 O--C.sub.6 H.sub.4 --                                                           99                                                  21           3-Cl--C.sub.6 H.sub.4 --                                                                   99                                                  22           3,5-Cl.sub.2 --C.sub.6 H.sub.3 --                                                          99                                                  23           3,5-(CH.sub.3).sub.2 --C.sub.6 H.sub.3                                                     99                                                  24           2-naphthyl   99                                                  ______________________________________                                         .sup.(1) Reaction run in benzene.                                        

EXAMPLE 25 Preparation of(S)-Tetrahydro-1-n-butyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole

A solution of the free base product from Example 1, Step B (20.1 g, 79.4mmol) and tri-n-butylboroxine (6.66 g, 26.5 mmol) in toluene (200 mL)was aged 0.5 hour at 20°-25° C., then heated at reflux for 16 hoursusing a Dean-Stark trap for water removal. The solution was concentrated(1 atm) to a volume of about 70 mL. The suitability of the catalyst wasdetermined by both capillary GC: (DB-1, 200° C.) <0.1%tri-n-butylboroxine (1.3 minute), <1% starting material (5.7minute), >98% product (9.7 minute), and ¹ H NMR: (CDCl₃) no startingmaterial δ4.25 (t). Based on the final volume of 70 mL, theconcentration of the oxazaborolidine was calculated to be 1.13M. Thetoluene solution, stored under an atmosphere of N₂ protected frommoisture, was used "as is" as a catalyst for the enantioselectivereduction of ketones with borane.

For analysis, a portion of the toluene solution (5.00 mL) wasconcentrated in vacuo (50° C., 0.001 mBar) to afford 1.80 g of theproduct as a colorless oil: IR (CCl₄) 3060, 3020, 2960, 2930, 2880,1480, 1440, 1240, 1000 cm⁻¹ ; ¹ H NMR (0.2M in CDCl₃) δ7.65-7.45 (m, 2H,Ar--H), 7.45-7.05 (m, 8H, Ar--H), 4.35 (dd, J=5.6, 9.9 Hz, 1H, C3a--H),3.45-3.30 (m, 1H, C6--H), 3.15-3.00 (m, 1H, C6--H), 1.90-1.25 (m, 7H,C4--H, C5--H₂, C2'--H₂, C3'--H₂), 1.05-1.70 (m, 6H, C4--H, C1'--H₂,C4'--H₃); ¹¹ B NMR (CDCl₃) δ34.3; .sup. 13 C NMR (0.2M in CDCl₃) δ147.8,144.1 (C1", C1'"), 128.1, 127.7 (C3", C3'", C5", C5'"), 127.1, 126.5(C4", C4'"), 126.22, 126.16 (C2", C2'", C6", C6'"), 87.4 (C3), 73.1(C3a), 42.8 (C6), 30.2 (C4), 26.9 (C2'), 26.5 (C5), 25.7 (C3'), 14.0(C4').

Anal. Calcd for C₂₁ H₂₆ BNO: C, 79.01; H, 8.21; N, 4.39. Found: C,78.58; H, 8.37; N, 4.37.

EXAMPLE 26 Preparation of(S)-Tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole

A solution of the free base product of Example 1, Step B (10.3 g, 40.7mmol) and triphenylboroxine (4.25 g, 13.6 mmol) in toluene (100 mL) wasaged 0.5 hour at 20°-25° C., then heated at reflux for 16 hours using aDean-Stark trap for water removal. The solution was concentrated (1 atm)to a volume of 47 mL. The suitability of the catalyst was determined byboth capillary GC: (DB-1, 160° C. for 3 minute, then 10° C./minute to300° C.) <0.1% benzophenone (2.6 minute), <1% starting material (7.5minute), <1% triphenylboroxine (10.8 minute), >98% oxazaborolidineproduct (14.2 minute), and ¹ H NMR: (CDCl₃) no starting material δ4.25(t). Based on the final volume of 47 mL, the concentration ofoxazaborolidine product was calculated to be 0.87M. The toluenesolution, stored under an atmosphere of N₂ protected from moisture, wasused "as is" as a catalyst for the enantioselective reduction of ketoneswith borane.

For analysis, a portion of the toluene solution (5.00 mL) wasconcentrated in vacuo (50° C., 0.001 mBar) to afford 1.48 g of theproduct as a colorless glass: IR (CCl₄) 3060, 3020, 2960, 2870, 1595,1445, 1300, 1000 cm⁻¹ ; ¹ H NMR (0.2M in CDCl₃) δ8.05-7.95 (m, 2H,Ar--H), 7.70-7.60 (m, 2H, Ar--H), 7.55-7.15 (m, 11H, Ar--H), 4.65 (dd,J=5.5, 9.7 Hz, 1H, C3a--H), 3.70-3.55 (m, 1H, C6--H), 3.45-3.30 (m, 1H,C6--H), 2.05-1.75 (m, 3H, C4--H, C5--H₂), 1.05-0.90 (m, 1H, C4--H); ¹¹ BNMR (CDCl₃) δ30.8; ¹³ C NMR (0.2M in CDCl₃) δ147.4, 143.8 (C1", C1'"),134.6 (C2', C6'), 130.3 (C4'), 128.2, 127.77 (C3", C3'", C5", C5'"),127.85 (C3', C5'), 127.2, 126.7 (C4", C4'"), 126.41, 126.35 (C2", C2'",C6", C6'"), 87.7 (C3), 74.4 (C3a), 43.8 (C6), 30.0 (C4), 27.6 (C5).

Anal. Calcd for C₂₃ H₂₂ BNO: C, 81.43; H, 6.54; N, 4.13. Found: C,81.35; H, 6.56; N, 4.12.

Employing the procedure substantially as described in Example 26, butsubstituting for the triphenylboroxine used therein, comparable amountsof triarylboroxines described in Table III, there were produced theB-aryl oxazaborolidines also described in Table III: ##STR16##

                  TABLE III                                                       ______________________________________                                        Example    R              Purity (%)                                          ______________________________________                                        27         4-F--C.sub.6 H.sub.4 --                                                                      98                                                  28         4-Cl--C.sub.6 H.sub.4 --                                                                     97                                                  29         4-CH.sub.3 --C.sub.6 H.sub.4 --                                                              99                                                  30         4-CF.sub.3 --C.sub.6 H.sub.4 --                                                              97                                                  31         4-CH.sub.3 O--C.sub.6 H.sub.4 --                                                             97                                                  32         2,4,6-(CH.sub.3).sub.3 --C.sub.6 H.sub.2 --                                                  97                                                  ______________________________________                                    

EXAMPLE 33 Preparation of(S)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole--boranecomplex

To a mechanically stirred solution of the oxazaborolidine decribed inExample 13 (1.28M in toluene) (20.0 mL, 25.6 mmol) at 20° C. was addedborane-methyl sulfide (10M, 5.0 mL, 50 mmol). The solution was stirredat 20° C. for 12 hours with a nitrogen sweep to remove dimethyl sulfide.The thick white mixture was filtered, and the product cake washed withdry toluene (10 mL). The product was dried in vacuo (20° C., 0.01 mBar)to afford 6.04 g (81% yield) of a white crystalline solid. m.p.122°-130° C. (dec). ¹ H NMR (CDCl₃) δ7.6 (m, 2H, Ar--H), 7.15-7.40 (m,8H, Ar--H), 4.65 (t, J=7.9 Hz, 1H, C3a--H), 3.4 (m, 1H, C6--H), 3.2 (m,1H, C6--H), 1.9 (m, 2 H, C5--H₂), 1.7 (m, 1H, C4--H), 1.3 (m, 1H,C4--H), 2.1-0.8 (very br, 3H, BH₃), 0.78 (s, 3H, B--CH₃). ¹³ C NMR(CDCl₃) δ144.6, 143.5 (C1', C1"), 128.3, 128.2 (C3', C5', C3", C5"),127.4, 127.1 (C4', C4"), 125.4, 125.0 (C2', C6', C2", C6"), 90.6 (C3),76.2 (C3a), 57.7 (C6), 31.4 (C4), 25.0 (C5).

Anal. Calcd for C₁₈ H₂₃ B₂ NO: C, 74.29; H, 7.97; N, 4.81. Found: C,xx.xx; H, x.xx; N, x.xx.

The following reaction scheme is described in Example 34, whichillustrates the utility of the oxazaborolidine catalysts, particularlyin Step E describing the reduction of 9 to 10. ##STR17##

EXAMPLE 34S-(+)-5,6-Dihydro-4-(2-methylpropyl)amino-4H-thieno-[2,3-b]-thiopyran-2-sulfonamide-7,7-dioxideSteps A and B: Preparation of 3-(2-thienylthio)propanoic acid (7)

In a 2-L, three-neck round-bottom flask fitted with a thermometer,nitrogen inlet, mechanical stirrer and addition funnel was placedthiophene (64 mL, 799 mmol; Caution: stench) and sieve dried THF (400mL, residual water ≦120 μg/mL). The solution was cooled to 0°-5° C. and1.6M n-butyllithium (470 mL, 751 mmol) was added at such a rate as tomaintain the temperature at <20° C. The reaction was stirred for 1 hourat 0°-5° C., and was used immediately in the next sequence. To thecooled reaction mixture (0°-5° C.) was added sulfur (24 g, 750 mmol)portionwise while maintaining the temperature at <20° C. The reactionwas stirred for an additional 2.0 hours at 0°-5° C. after whichnitrogen-purged water (300 mL) was added at such a rate as to maintainthe temperature at <18° C. The addition of sulfur was highly exothermic.(Note: the 2-mercaptothiophene and its anion (6) can air-oxidize to thecorresponding disulfide. Therefore, solutions of 6 must be deoxygenatedand stored under a nitrogen atmosphere). Solids may form initially uponaddition of water to the solution of 6 but eventually dissolve. Thesolution of 6 was titrated for total base. The yield of thiophene to 6based on titration was 98%.

In a 1-L, three-neck, round-bottom flask fitted with an addition funnel,thermometer, nitrogen sweep and mechanical overhead stirrer was prepareda solution of potassium carbonate (46.5 g, 337 mmol) in nitrogen-purgedwater (85 mL). To this solution was added solid 3-bromopropionic acid(116 g, 736 mmol) at such a rate as to control foaming (CO₂ evolution).The mixture was stirred until a clear solution was obtained. Thetemperature increased from 23° C. to 50° C. during the dissolution ofpotassium carbonate. (Caution: foaming occurs during the addition). Thesolution of 6 was cooled to 10° C. and the aqueous solution of potassium3-bromopropionate was added at such a rate as to maintain thetemperature at 0°-5° C. The reaction was stirred for 24 hours at ambienttemperature. The layers were separated and the aqueous layer was washedtwice with toluene (100 mL portions) to remove neutral organicimpurities. The aqueous layer was then cooled to 10° C. and stirred withtoluene (300 mL) as aqueous HCl (125 mL, 6N) was added, maintaining thetemperature at <14° C. (pH<1). The organic layer was separated and theaqueous layer extracted with additional toluene (300 mL). The organiclayers were combined and dried azeotropically under vacuum to a volumeof 500 mL and residual water content of ≦2.5 mg/mL. The solution wasstored at 0°-5° C. overnight. A small amount of the carboxylic acid wasisolated and characterized as its tert-butylammonium salt: m.p.110°-112° C. IR (CHCl₃): 3400-2300 br s (OH), 2980 m, 2630 m, 2200 w,1635 m, 1580 br s (C═O), 1480 w, 1390 s, 1300 m, 1270 m, 990 w, 930 w,850 w. ¹ H NMR: δ8.36 (br s, NH₃ ⁺), 7.29 (d, J=5.4, H_(5')), 7.07 (d,J=3.5, H_(3')), 6.93 (dd, J=5.4, 3.5, H_(4')), 2.99 (m, C₂ H₂), 2.43 (m,C₃ H₂), 1.27 (s, C(CH₃)₃). ¹³ C NMR: δ177.9 (C₁), 134.5 (C_(2')), 133.5,129.0, 127.4 (C_(3'), C_(4'), C_(5')), 50.6 (C(CH₃)₃), 38.4, 35.6 (C₂,C₃), 27.8 (C(CH₃)₃).

Anal. Calcd for C₁₁ H₁₉ NO₂ S₂ : C, 50.54; H, 7.33; N, 5.36. Found: C,50.53; H, 7.12; N, 5.27.

Step C: Preparation of 5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one (8)

In a 2-L three-neck round-bottom flask fitted with an overheadmechanical stirrer, thermometer, addition funnel, reflux condenser, andnitrogen bubbler vented through an acid-vapor scrubber was placed thetoluene solution of 7 (130.7 g, 695 mmol). The reaction mixture wasbrought to an initial temperature of 20° C. and trifluoroaceticanhydride (161 g, 765 mmol) was added over 5 minutes to the stirredsolution of 7. The reaction was then heated to 35°-38° C. and stirredfor about 1.5 hours. The reaction was then slowly added to water (500mL) maintaining the temperature at <25° C. A pH probe was placed in thevessel and the mixture was titrated to pH 7.0 with 50% sodium hydroxide(123 g, 1.53 mole). The layers were separated and the aqueous phase wasextracted once with toluene (200 mL). The combined organic extracts werethen concentrated under vacuum (43 mbar) to a volume of 200 mL and thendiluted to 1.2 L with ethyl acetate for the next step (oxidation). Asmall sample was chromatographed to obtain the following data: R_(f)=0.29 (85:15 hexane:ethyl acetate). m.p. 61°-62° C. IR (CHCl₃): 3120 w,3090 w, 3010 m, 2930 w, 1660 s (C═O), 1500 m, 1390 s, 1315 w, 1280 w,1265 m, 1190 w, 1035 w, 890 w. ¹ H NMR: δ7.42 (d, J=5.4, H₂); 6.98 (d,J=5.4, H₃); 3.33 (m, C₅ H₂); 2.82 (m, C₆ H₂). ¹³ C NMR: δ188.9 (C₄),150.9, 135.0 (C_(3a), C_(7a)), 126.1, 121.8 (C₂, C₃), 38.1 (C₆), 30.0(C₅).

Anal Calcd for C₇ H₆ OS₂ : C, 49.39; H, 3.55; S, 37.66. Found: C, 49.56;H, 3.58; S, 37.68.

Step D: Preparation of5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (9)

The ethyl acetate/toluene solution of ketone 8 (118 g, 765 mmol in 1.2 Lof 5:1 v:v EtOAc/toluene) was charged to a 5-L three-neck round-bottomflask equipped with an overhead mechanical stirrer, 250-mLpressure-equalizing dropping funnel, and thermocouple temperature probe.The mixture was stirred and water (35 mL) was added to saturate theorganic phase. A solution of sodium tungstate dihydrate (11.7 g, 77mmol) dissolved in water (35 mL) was then added (Caution: there is aninduction period of several minutes before an exotherm). The mixture washeated to 35° C. and hydrogen peroxide (30%, 250 mL, 2.43 mole) wasadded over 45 minutes. The temperature of the reaction was allowed torise to 55°-58° C. and was maintained there, initially with cooling andsubsequently with heating. The reaction temperature was maintained at55°-58° C. until judged complete by HPLC: column A, (1 mL/minute, 50:500.01M H₃ PO₄ in H₂ O:CH₃ CN, 240 nm) R_(t) (8) 6.18 minutes, (9) 4.07minutes. On completion the mixture was cooled to 0°-5° C. and excesshydrogen peroxide was decomposed by the slow addition of aqueous sodiumsulfite (205 g, 1.63 mole dissolved in 700 mL water). The temperature ofthe reaction mixture was maintained at <20° C. When the reaction mixturetested negative for peroxide to acidified starch-iodide paper, thelayers were separated. The upper organic layer was concentrated undervacuum at 45° C. bath temperature to a volume of 400 mL. Hexanes (400mL) were then added over about 10 minutes and the batch was aged for onehour. The product was filtered, washed with hexanes, and dried undervacuum at 60° C. with a nitrogen sweep to constant weight. The yield ofcrude ketosulfone 9 was 113 g (76% from 3-bromopropionic acid). Crudeketosulfone was then recrystallized from methanol using the followingprocedure. Crude ketosulfone (113 g) was dissolved in anhydrous methanol(3 L) at 55°-60° C. The solution was cooled to 40° C. and 10 g of CalgonADP carbon was added. The mixture was aged at 40° C. for a minimum of 4hours. The batch was then filtered warm at 40° C. through a well-washedpad of SuperCel. The filter cake was washed with methanol (2×500 mL) at40° C. and the filtrates were combined. The batch was then concentratedunder vacuum to a volume of 500 mL and aged at 0°-5° C. for 4 hours.Crystallization ensued during concentration. The batch was filtered,washed with 75 mL cold methanol, sucked dry under nitrogen, and driedunder vacuum (100 Torr) at 80° C. with a nitrogen sweep for 12 hours.The recovery yield was 100 g (89%) assayed δ99.6 wt % by HPLC against anexternal stand ard. R_(f) =0.30 (dichloromethane). m.p. 121°-121.5° C.IR (CHCl₃): 3120 w, 3100 w, 3020 m, 1690 s (C═O), 1500 w, 1410 m, 1390m, 1330 s (SO₂), 1310 m, 1285 m, 1260 m, 1190 s, 1155 s (SO₂), 1130 m,1090 m, 860 s, 820 w. ¹ H NMR: δ7.60 (d, J=5.1, H₂); 7.50 (d, J=5.1,H₃); 3.76 (m, C₅ H₂); 3.36 (m, C₆ H₂). ¹³ C NMR: δ186.3 (C₄), 147.2(C_(3a)), 139.3 (C_(7a)), 130.2 (C₂), 126.3 (C₃), 52.8 (C₆), 37.0 (C₅).MS (EI, 70 eV): 202 (M⁺, 35), 174 (38), 138 (15), 110 (100), 84 (30), 82(25).

Anal. Calcd for C₇ H₆ O₃ S₂ : C, 41.57; H, 2.99; S, 31.70. Found: C,41.49; H, 3.02; S, 31.60.

Step E: Preparation ofR-(+)-5,6-Dihydro-4H-thieno-[2,3-b]-thiopyran-4-ol-7,7-dioxide (10)

Ketosulfone 9 (50.0 g, 0.247 moles) was dissolved in tetrahydrofuran(700 mL) over 4 Å molecular sieves (20 g) and occasionally swirled untilthe residual water content was <40 μg/mL (about 2 hours). A 2-Lthree-neck round bottom flask fitted with a mechanical stirrer, nitrogeninlet tube, 500-mL addition funnel and teflon coated thermocouple probe,was charged with 9 (decanted from the sieves). To the solution was addedoxazaborolidine catalyst (R=CH₃, Ar=C₆ H₅) (14.4 mL of a 0.86M solutionin toluene). The resulting solution was cooled to -15° C. In a separatevessel borane-methyl sulfide (17.3 mL) was dissolved in drytetrahydrofuran (297 mL; residual water <40 μg/mL). The borane-methylsulfide solution was placed in the addition funnel and added to theketosulfone/catalyst solution at a rate to maintain the internaltemperature at -15° C. (about 30 minutes). After all of the borane wasadded, the reaction was aged for 30 minutes. An easily stirredprecipitate usually forms during the age. The reaction was quenched bythe cautious addition of 10 mL of methanol (Caution: there was asignificant induction period (1-2 minutes) before hydrogen was evolvedafter the initial methanol was added) maintaining the temperature at-10° C. After hydrogen evolution subsides, methanol (365 mL) was added.The reaction becomes homogeneous during the quench. After completeaddition of methanol, the reaction mixture was warmed to 20° C. andstirred for 12 hours. The resulting solution was concentrated atatmospheric pressure to about 125 mL. Methanol (375 mL) was added andthe resulting solution was concentrated at atmospheric pressure to 125mL to remove any remaining volatile boron species.

Amberlyst 15 resin (56 g, 100 mL dry) was suspended in methanol (100mL). (Caution: the slurry exotherms to about 40° C. without externalcooling and expands on wetting to about 1.5 times its initial volume).The slurry was poured into a 2.5×30 cm column and eluted with 1 L ofammonium hydroxide (15M) in methanol (6 vol %, about 1M) until theeluate was basic (pH about 11 when diluted 1:1 with water). The initialbrown eluate was discarded. The column was eluted with methanol (about500 mL) until the eluate was neutral. The methanol solution of(R)-hydroxy sulfone (about 50 g) and (S)-diphenylprolinol (3.13 g) wasfiltered through a pad of SuperCel. The cake was washed with methanol(2×50 mL) and the combined filtrates brought to a volume of 500 mL (10mL/g) with methanol. The filtered methanol solution was eluted throughthe column containing Amberlyst 15 (NH₄ ⁺) at 3.8 mL/minute collecting38 mL fractions. The column was rinsed with methanol (380 mL) to removeall of the product hydroxysulfone. The column was then eluted with 94:6(v/v) methanol/15M aqueous ammonia (400 mL) to elute diphenylprolinol.Fractions 3-21 containing (R)-hydroxysulfone (95:5 R:S, 49 g (98%),contaminated with less than 0.4% diphenylprolinol) were combined andconcentrated (recrystallization of this material from hexane/ethylacetate only serves to lower enantiomeric purity). Addition oftetrahydrofuran (500 mL) followed by concentration to 250 mL wasrepeated twice. Tetrahydrofuran was added to generate a solution of 10in a total volume of 500 mL for use in the next reaction. Fractions29-33 containing (S)-diphenylprolinol (<1:99 R:S, 3.0 g) were combinedand concentrated to afford a crystalline solid. The progress of thecolumn can be monitored by HPLC: column A (1 mL/minute, 60:40 0.01M KH₂PO₄ in H₂ O:CH₃ CN) R_(t) (9) 4.78 minutes (240 nm), (10) 3.30 minutes(240 nm), (diphenylprolinol) 5.60 minutes (210 nm). A small sample waschromatographed to obtain characterization data: R_(f) =0.07 (60:40hexane:ethyl acetate). [α]₅₈₉ ²¹ =+16.4° (c 0.210, MeOH). m.p. 89°-90°C. IR (CHCl₃): 3600 w (OH), 3550-3400 br w (OH), 3110 w, 3010 m, 2940 w,1520 w, 1400 m, 1305 s (SO₂), 1285 s, 1180 w, 1145 s (SO₂), 1125 s, 1100w, 1160 m, 1140 m, 970 w, 915 w, 890 w, 845 w, 825 m. ¹ H NMR: δ7.59 (d,J=5.1, H₂), 7.12 (d, J=5.1, H₃), 4.91 (ddd, J=10.0, 5.9, 1.5, H₄), 3.62(m, H₆), 3.31 (m, H₆), 2.75 (m, H₅), 2.55 (m, H₅, OH). ¹³ NMR: δ144.9(C_(3a)), 135.9 (C_(7a)), 130.5 (C₂), 127.0 (C₃), 63.5 (C₄), 49.1 (C₆),31.0 (C₅).

Anal. Calcd for C₇ H₈ O₃ S₂ : C, 41.16; H, 3.95; S, 31.39. Found: C,41.23; H, 3.93; S, 31.24.

Chiral Assay: To alcohol 10 (20 mg) in dry dichloromethane (2 mL) wasadded N,N-dimethylaminopyridine (12 mg, 1.0 equiv), triethylamine (14mL, 10 mg, 3.0 equiv) and(R)-(+)-a-methoxy-a-(trifluoro-methyl)phenylacetic acid chloride (Mosheracid chloride, 27 mg, 21 mL, 1.1 equiv, see General of ExperimentalSection). The mixture was stirred for 1-5 hours, as judged by TLC (EMSi-60, 6:4 hexane/EtOAc, R_(f) alcohol 10=0.10, R_(f) ester=0.60). Thereaction mixture was diluted with hexane (8 mL) and centrifuged (5minutes). The resulting clear yellow solution was eluted through a BakerSilica SPE (1 g) column (previously washed with 5 mL of hexane). Theinitial eluate was discarded, and 6:4 hexane/EtOAc (10 mL) was elutedand collected. The latter eluate was then analyzed by capillary GC oncolumn A: (15 psi, 200° C., isothermal) R_(t) ((R,R)-Mosher ester(major), 10.0 minutes; (R,S)-Mosher ester (minor), 10.4 minutes.Enantiomeric purity: >95:5.

Steps F and G: Preparation ofS-5,6-Dihydro-N-(2-methylpropyl)-4H-thieno[2,3-b]-thiopyran-4-amine-7,7-dioxide(12)

A 3-L three-neck flask fitted with a mechanical stirrer, nitrogen inlettube, 500-mL addition funnel and teflon coated thermocouple probe wascharged with a slurry of sodium acetylide in xylene/light mineral oil(Aldrich, 71.9 g, 0.270 mol of an 18% slurry) and was well mixed with400 mL of tetrahydrofuran. Hydroxysulfone 10 (50.0 g, 0.245 moles)dissolved in dry tetrahydrofuran (500 mL, see above; residual watercontent should be <100 μg/mL) and placed in the addition funnel. Thesolution was cooled to 15° C. and the solution of 10 was added to thesodium acetylide over about 5 minutes. (Caution: sodium acetylide ismoisture sensitive and generates acetylene upon addition of water). Theresulting suspension was stirred at 20° C. for 2 hours. During the age,the fine slurry of sodium acetylide was converted to the easily stirred,coarse, crystalline sodium salt of the hydroxysulfone. (Thedeprotonation can be monitored by removing a 1 mL aliquot and adding itto excess toluenesulfonyl chloride (45 mg, 0.24 mmol) in 1 mL oftetrahydrofuran and monitoring by TLC: 60:40 hexane:ethyl acetate; R_(f): hydroxysulfone 10, 0.07; tosylate 11, 0.37). The resulting slurry wascooled to -15° C. Toluenesulfonyl chloride (51.3 g, 0.269 mol) wasdissolved in 250 mL of tetrahydrofuran and placed in the additionfunnel. The toluenesufonyl chloride/tetrahydrofuran solution was addedto the sodium salt at a rate to maintain the internal temperature below-10° C. (about 10 minutes). The resulting mixture was aged at -10° C.for 2 hours. The tosylation can be followed by TLC (60:40 hexane:ethylacetate; R_(f) : tosylate 11, 0.37; hydroxysulfone 10, 0.07). The sodiumsalt of the hydroxysulfone dissolved during the age and the reactionusually turned dark green. (Note: tosylate 11 should not be isolatedsince it readily hydrolyzes to racemic 10 in water). Dry (residual water<100 μg/mL) isobutylamine (250 g, 340 mL, 3.43 mol) was added over 5minutes. The resulting mixture was warmed to 20° C. and aged for 14hours. (This reaction was monitored by TLC: 60:40 hexane:ethyl acetate;R_(f) : tosylate 11, 0.37; amine 12, 0.25). The resulting mixture wascooled to -15° C. and aqueous hydrochloric acid (1.54 L, 2N) was addedat a rate to maintain the internal temperature at or below 5° C. (about30 minutes). The resulting pH was about 2.5. The solution wasconcentrated to about 1.6 L to remove most (90%) of the tetrahy drofuranand extracted with isopropyl acetate (2×600 mL). The aqueous phase wascooled to 0° C. and sodium hydroxide (120 mL, 5N) was added at a rate tomaintain the internal temperature below 5° C. (about 5 minutes). Theresulting pH was about 10 and the reaction mixture became cloudy uponaddition of sodium hydroxide. The resulting mixture was extracted twicewith isopropyl acetate (600 mL). The organic layers were combined andconcentrated to about 120 mL. Isopropanol (600 mL) was added and themixture was concentrated to 100 mL. A second flush was performed toremove the isopropyl acetate. (Solubility of amine 12 in isopropa nol:2.5 mg/mL at -20° C.; 7.3 mg/mL at 0° C.; 28.3 mg/mL at 20° C.; 151mg/mL at 45° C.). Isopropanol was added to bring the volume to about 1 Land the resulting solution was warmed to 55°-60° C. and Calgon ADP (5 g)decolorizing carbon was added. The mixture was stirred at 50° C. for 4hours. The resulting mixture was filtered (at 50° C.) through prewashedSuperCel. The filtered solution was concentrated to 0.86 L (14 mL/gamine) and allowed to cool slowly to room temperature. The resultingsuspension was cooled to 0° C. and aged for 2 hours. The suspension wasfiltered, washed twice with 150 mL of 0° C. isopropanol and dried invacuo at 45° C. for 12 hours to yield 47 g (73%) of amine 12(R=2-methylpropyl) as off white crystals.

Data for 12: R_(f) =0.25 (60:40 hexane:ethyl acetate). [α]₅₈₉ ²² =-8.68°(c 0.316, MeOH). m.p. 86°-86.5° C. IR (CHCl₃): 3110 w, 3010 m, 2960 m,2950 sh, 2900 w, 2870 w, 2830 w, 1520 w, 1460 m, 1400 m, 1365 w, 1305 s(SO₂), 1280 m, 1140 s (SO₂), 1090 m, 1055 w, 890 w, 850 w, 830 w. ¹ HNMR: δ7.53 (d, J=5.0, H₂), 7.08 (d, J=5.0, H₃), 3.91 (dd, J=6.3, 4.1,H₄), 3.68 (ddd, J=13.6, 9.8, 2.8, H₆), 3.27 (ddd, J=9.3, 8.8, 2.6, H₆),2.55 (m, C₅ H₂, C_(1') H₂), 1.68 (nine lines, J=6.6), 0.92 (d, J=6.8).¹³ C NMR: δ146.0 (C_(3a)), 135.6 (C_(7a)), 129.7 (C₂), 127.1 (C₃), 55.0(C_(1')), 52.6 (C₄), 49.6 (C₆), 28.8 (C_(2')), 27.8 (C₅), 20.6, 20.5(2×CH₃).

Anal. Calcd for C₁₁ H₁₇ NO₂ S₂ : C, 50.94; H, 6.61; N, 5.40; S, 24.72.Found: C, 51.00; H, 6.64; N, 5.30; S, 24.50.

Chiral Assay: To amine 12 (10 mg) in dry ethyl acetate (1 mL) was addedtrifluoroacetic anhydride (20 mL). The mixture was stirred for 1-5minutes, as judged by TLC (EM Si-60, 6:4 hexane/EtOAc, R_(f) : amine 12,0.30; amide, 0.50). The reaction mixture was concentrated to dryness andthen diluted with tetrahydrofuran (2 mL). The resulting clear yellowsolution was eluted through a Baker quaternary amine SPE (1 g) column(previously washed with 5 mL of isopropanol). The eluate was collected,and 88:11:1 hexane/tetrahydrofuran/isopropanol (20 mL) was eluted andcollected. The eluate was then analyzed by normal phase HPLC (250 nm):column B (2.0 mL/minute, 88:11:1 hexane:tetrahydrofuran: isopropanol,isocratic): R_(t) : (R)-TFA-12 10.65 minutes; (S)-TFA-12 12.82 minutes.Enantiomeric purity >99:1.

Step H: Preparation ofS-(+)-5,6-Dihydro-4-(2-methylpropyl)amino-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxidemonohydrochloride hemihydrate (13)

A 1-L round-bottom flask fitted with a mechanical stirrer, nitrogeninlet and septum was charged with fuming sulfuric acid (12-20% SO₃ in H₂SO₄, 125 mL). (Caution: fuming sulfuric acid (oleum) is extremelycorrosive). The solution was cooled to -15° C. and amine 12(R=2-methylpropyl) (25 g, 96.4 mmol) was added portionwise at a rate tomaintain the temperature <0° C. (Caution: the addition is exothermic).After stirring the resultant solution for 2 hours at 5°-8° C., thionylchloride (375 mL, 611 g, 5.14 mol) was added and the mixture wasrefluxed for 3 hours. The thionyl chloride was removed by distillationand the resulting oil was cooled to 0° C. A 5-L round-bottom flaskfitted with a mechanical stirrer, 250-mL pressure equalizing additionfunnel (with a teflon tube attached to the bottom that reached below thesurface of the contained liquid) and nitrogen inlet was charged withconcentrated aqueous ammonia (800 mL) and tetrahydrofuran (800 mL) andcooled to -15° C. The addition funnel was charged with the sulfuric acidsolution of the sulfonyl chloride. The sulfuric acid solution was slowlyadded (subsurface) to the ammonia mixture at a rate to maintain thetemperature below 0° C. (about 1 hour). (Caution: addition of strongacid to strong base is exothermic and spattering may occur). Aftercomplete addition, the resulting mixture was stirred at 0° C. for 30minutes. The resulting pH was 10. The resulting suspension was filteredand the filter cake washed twice with tetrahydrofuran (600 mL). Thefiltrate was concentrated to remove tetrahydrofuran and extracted twicewith ethyl acetate (600 mL). The organic layers were combined,concentrated to 375 mL and stirred well as concentrated hydrochloricacid (12 mL, 145 mmol) was slowly added. The mixture was concentratedunder vacuum at 45° C. (bath temperature) to remove water, replacingethyl acetate as necessary, until a solution with a water content of<0.1 mg/mL was attained at a volume of about 350 mL. The crystallizedmixture was allowed to cool and stirred at ambient temperatureovernight. The slurry was filtered and washed with two bed volumes ofethyl acetate. The white solid was dried under vacuum at 45° C. toafford 26 g of 13 (R=2-methylpropyl) hydrochloride. The salt could berecrystallized from water as follows: 13 (R=2-methylpropyl)hydrochloride (25 g, 73 mmol) was dissolved in water (50 mL) at 90° C.The mixture was well stirred and activated carbon (Darco KB, 2.5 g) wasadded to the hot mixture. After stirring for 2 hours, the mixture wasfiltered hot (85°-90° C.) through a washed bed of SuperCel and thefilter cake washed with 10 mL of boiling water. The combined filtrateand wash was allowed to slowly cool to 40°-50° C. and held at 40°-50° C.until crystallization occurred. After stirring for 1 hour at 55° C.after crystallization occurred, the mixture was cooled to 3° C. and agedfor 1 hour. The resulting mixture was filtered and the filter cakewashed with cold water (10 mL). The product was dried under vacuum at45° C. with a nitrogen sweep to afford 21 g (71%) of 13(R=2-methylpropyl) hydrochloride. This sequence can be monitored byHPLC: column A, (1 mL/minute, 55:45 0.01M K₂ HPO₄ in H₂ O:CH₃ CN, 240nm) R_(t) : sulfonic acid, 2.37 minutes; (13), 6.34 minutes; (12), 8.54minutes; tricycle byproduct, 10.17 minutes. [α]₅₈₉ ²⁵ =+49 (c 0.50,MeOH). m.p. 222° C. (dec). IR (KBr): 3350 w (NH), 2950 s, 2800-2300 w(NH₂ ⁺), 1620 w, 1590 w, 1540 m, 1466 w, 1420 w, 1400 w, 1350 s (SO₂),1340 s (SO₂), 1300 s (SO.sub. 2), 1160 s (SO₂), 1145 s (SO₂), 1050 m,1020 m, 910 w, 880 m, 740 m, 700 w. ¹ H NMR (DMSO-d₆): δ9.82 (br s, C₄NH₂ ⁺), 8.20 (s, SO₂ NH₂), 8.16 (s, C₃ H), 4.80 (br s, C₄ H), 3.94 (m,C₆ H₂), 3.83 (s, H₂ O), 2.82 (m, C₅ H₂, C_(1') H₂), 2.15 (septet, J=6.6,C_(2') H), 0.98 (d, J=6.6, CH₃), 0.96 (d, J=6.6, CH₃). ¹³ C NMR(DMSO-d₆): δ149.4 (C₂), 141.8 (C_(7a)), 137.5 (C_(3a)), 129.8 (C₃), 51.2(C₆), 50.9 (C₄), 48.3 (C_(1')), 25.5 (C_(2')), 23.7 (C₅), 20.3, 20.0(2×CH₃). HRMS (free base, EI, 90 eV) Calcd for C₁₁ H₁₈ N₂ O₄ S₂ :338.0429. Found: 338.0430.

Anal. Calcd for C₁₁ H₁₉ ClN₂ O₄ S₃ 0.5 H₂ O: C, 34.41; H, 5.25; N, 7.30;S, 25.05; Cl, 9.23. Found: C, 34.55; H, 5.20; N, 7.21; S, 24.89; Cl,9.50.

Employing procedures substantially as described in Example 34 Step E butsubstituting for the ketone 9 sub strate and the oxazaborolidine usedtherein, the ketone and oxazaborolidine described in Table IV, therewere produced the corresponding secondary alcohols in the enantiometricratios shown therein.

                                      TABLE IV                                    __________________________________________________________________________     ##STR18##                                                                     ##STR19##                                                                    R        Ar         9  14  15 16  17                                          __________________________________________________________________________    CH.sub.3 C.sub.6 H.sub.5                                                                          98:2                                                                             99:1                                                                              82:18                                                                            98:2                                                                              97:3                                        CH.sub.3 4-FC.sub.6 H.sub.4                                                                       97:3                                                                             84:16                                                                             85:15                                                                            97:3                                                                              94:6                                        CH.sub.3 4-ClC.sub.6 H.sub.4                                                                      97:3                                                                             90:10                                                                             82:18                                                                            96:4                                                                              94:6                                        CH.sub.3 4-CH.sub.3C.sub.6 H.sub.4                                                                96:4                                                                             86:14                                                                             83:17                                                                            95:5                                                                              95:5                                        CH.sub.3 4-CF.sub.3C.sub.6 H.sub.4                                                                98:2                                                                             95:5                                                                              88:12                                                                            96:4                                                                              96:4                                        CH.sub.3 4-t-BuC.sub.6 H.sub.4                                                                    95:5                                                                             93:7                                                                              84:16                                                                            98:2                                                                              91:9                                        CH.sub.3 4-CH.sub.3 OC.sub.6 H.sub.4                                                              97:3                                                                             95:5                                                                              84:16                                                                            95:5                                                                              97:3                                        CH.sub.3 3-ClC.sub.6 H.sub.4                                                                      96:4                                                                             93:7                                                                              86:14                                                                            96:4                                                                              98:2                                        CH.sub.3 3,5-Cl.sub.2C.sub.6 H.sub.3                                                              96:4                                                                             90:10                                                                             80:20                                                                            92:8                                                                              95:5                                        CH.sub.3 3,5-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                      96:4                                                                             97:3                                                                              86:14                                                                            96:4                                                                              97:3                                        CH.sub.3 2-naphthyl 96:4                                                                             89:11                                                                             82:18                                                                            96:4                                                                              96:4                                        n-C.sub.4 H.sub.9                                                                      C.sub.6 H.sub.5                                                                          93:7                                                                             96:4                                                                              88:12                                                                            95:5                                                                              98:2                                        C.sub.6 H.sub.5                                                                        C.sub.6 H.sub.5                                                                          98:2                                                                             86:14                                                                             77:23                                                                            91:9                                                                              97:3                                        4-FC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                          99:1                                                                             94:6                                                                              76:24                                                                             88:12                                                                            97:3                                        4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                          98:2                                                                             87:13                                                                             72:38                                                                             86:14                                                                            94:6                                        4-CH.sub.3C.sub.6 H.sub.4                                                              C.sub.6 H.sub.5                                                                          99:1                                                                             94:6                                                                              81:19                                                                            92:8                                                                              97:3                                        4-CH.sub.3 OC.sub.6 H.sub.4                                                            C.sub.6 H.sub.5                                                                          97:3                                                                             85:15                                                                             76:24                                                                            92:8                                                                              95:5                                        __________________________________________________________________________

EXAMPLE 35 Preparation of(R)-(+)-5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-ol-7,7-dioxide (10)

To a magnetically stirred solution of5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (9) (1.00 g,4.94 mmol) in dry THF (14 mL) was added (S)-diphenylprolinol--boranecomplex from Example 12 (132 mg, 0.494 mmol). The solution was cooled to-15° C. and a solution of borane-methyl sulfide (10M, 0.4 mL, 4.0 mmol)in dry THF (6.8 mL) was added at a rate to maintain the internaltemperature at -15° C. The solution was stirred at -15° C. for 1 hourthen at 22° C. for 6 hours. The product was isolated by the methoddecribed in Example 34 Step E. The enantiomeric ratio of the purifiedproduct was 95.5.

EXAMPLE 36 Preparation of(R)-(+)-5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-ol-7,7-dioxide (10)

To a magnetically stirred solution of5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (9) (1.00 g,4.94 mmol) in dry THF (14 mL) was added(S)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole--borane complex from Example 33 (144mg, 0.494 mmol). The solution was cooled to -15° C. and a solution ofborane-methyl sulfide (10M, 0.4 mL, 4.0 mmol) in dry THF (6.8 mL) wasadded at a rate to maintain the internal temperature at -15° C. Thesolution was stirred at -15° C. for 1 hour. The product was isolated bythe method decribed in Example 34 Step E. The enantiomeric ratio of thepurified product was 99:1.

What is claimed is:
 1. A process for the preparation of a compound of structural formula: ##STR20## wherein: n is 1 or 2;R¹ and R² independently are hydrogen, C₁₋₃ alkyl, or joined together represent, with the carbons to which they are attached, a benzo group or a double bond; Ar is1) 2-naphthyl, 2) phenyl, 3) phenyl substituted in 3- and/or 4-position with one or more of:i) halo, ii) C₁₋₄ alkyl, iii) CF₃, or iv) C₁₋₄ alkoxy;which comprises the reaction of a compound of structural formula: ##STR21## with an aryl Grignard reagent wherein aryl is 2-naphthyl, phenyl or phenyl substituted in the meta- and/or para- positions with one or more of chloro, fluoro, C₁₋₄ alkyl, CF₃ or C₁₋₄ alkoxy.
 2. The process of claim 1 wherein the aryl Grignard reagent is a phenyl magnesium halide.
 3. The process of claim 2 wherein the reaction is conducted in an ethereal solvent at about -25° to 10° C.
 4. The process of claim 3, wherein the ethereal solvent is THF.
 5. The process of claim 1, wherein R¹ and R² are hydrogen, n is 1, and Ar is phenyl.
 6. The process of claim 2, wherein R¹ and R² are hydrogen and n is
 1. 7. The process of claim 3, wherein R¹ and R² are hydrogen and n is
 1. 